A randomized phase I trial evaluating the effects of inhaled 50-50% N2 O-O2 on remifentanil-induced hyperalgesia and allodynia in human volunteers.

Abstract

Opioids are known to relieve pain, and also aggravate pre-existing hyperalgesia. In animal studies, the N-methyl-d-aspartate-receptor antagonist nitrous oxide (N2 O) was able to prevent hyperalgesia. The present study evaluated the effect of N2 O on hyperalgesia after remifentanil infusion in healthy volunteers. Twenty-one healthy volunteers were enrolled in this placebo-controlled cross-over study. Transcutaneous electrical stimulation at high current densities induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions: (1) 50-50% N2 -O2 and i.v. saline; (2) 50-50% N2 -O2 and i.v. remifentanil 0.1μg/kg/min; (3) 50-50% N2 O-O2 and i.v. saline; (4) 50-50% N2 O-O2 and i.v. remifentanil 0.1μg/kg/min. Inhaled gas mixtures lasted for 60min, i.v. drug administration for 30min. Visual analogue scale pain intensity, areas of pinprick hyperalgesia and touch-evoked allodynia were assessed repeatedly for 160min. Data of 19 volunteers were analysed. There were significant time and treatment effects regarding areas of hyperalgesia and allodynia (p<0.02). The area of hyperalgesia was significantly reduced in the N2 O+remifentanil session compared to the remifentanil session (35.88±22.37 vs. 43.55±18.48cm(2) , p=0.004). The area of allodynia was significantly reduced in the N2 O+remifentanil session compared to the remifentanil session (29.95±16.15 vs. 34.80±15.35cm(2) , p=0.008). The pain intensity was significantly reduced in the N2 O+remifentanil session compared to the remifentanil session (37.96±12.78 vs. 42.15±13.34mm, p<0.0001). Nitrous oxide significantly reduced hyperalgesia, allodynia and pain intensity aggravated after remifentanil administration in a human volunteer model. WHAT DOES THIS STUDY ADD?: This study brings the evidence that N2 O reduces the remifentanil aggravated secondary hyperalgesia in human volunteers exposed to a well-known model of electrical pain. N2 O was able to oppose the hyperalgesia, the allodynia and the pain intensity consecutive to remifentanil use in this specific pain model.